Yau Thomas, Cheng Paul N, Chan Pierre, Chen Li, Yuen Jimmy, Pang Roberta, Fan Sheung Tat, Wheatley Denys N, Poon Ronnie T
Department of Medicine, The University of Hong Kong, Hong Kong, China,
Invest New Drugs. 2015 Apr;33(2):496-504. doi: 10.1007/s10637-014-0200-8. Epub 2015 Feb 10.
This study was designed to evaluate the efficacy, safety profile, pharmacokinetics, pharmacodynamics and quality of life of pegylated recombinant human arginase 1 (Peg-rhAgr1) in patients with advanced hepatocellular carcinoma (HCC). Patients were given weekly doses of Peg-rhAgr1 (1600 U/kg). Tumour response was assessed every 8 weeks using RECIST 1.1 and modified RECIST criteria. A total of 20 patients were recruited, of whom 15 were deemed evaluable for treatment efficacy. Eighteen patients (90%) were hepatitis B carriers. Median age was 61.5 (range 30-75). Overall disease control rate was 13%, with 2 of the 15 patients achieving stable disease for >8 weeks. The median progression-free survival (PFS) was 1.7 (95% CI: 1.67-1.73) months, with median overall survival (OS) of all 20 enrolled patients being 5.2 (95% CI: 3.3-12.0) months. PFS was significantly prolonged in patients with adequate arginine depletion (ADD) >2 months versus those who had ≤2 months of ADD (6.4 versus 1.7 months; p = 0.01). The majority of adverse events (AEs) were grade 1/2 non-hematological toxicities. Transient liver dysfunctions (25%) were the most commonly reported serious AEs and likely due to disease progression. Pharmacokinetic and pharmacodynamic data showed that Peg-rhAgr1 induced rapid and sustained arginine depletion. The overall quality of life of the enrolled patients was well preserved. Peg-rhAgr1 is well tolerated with a good toxicity profile in patients with advanced HCC. A weekly dose of 1600 U/kg is sufficient to induce ADD. Significantly longer PFS times were recorded for patients who had ADD for >2 months.
本研究旨在评估聚乙二醇化重组人精氨酸酶1（Peg-rhAgr1）在晚期肝细胞癌（HCC）患者中的疗效、安全性、药代动力学、药效学及生活质量。患者每周接受Peg-rhAgr1剂量为1600 U/kg。每8周使用RECIST 1.1和改良RECIST标准评估肿瘤反应。共招募20例患者，其中15例被认为可评估治疗疗效。18例患者（90%）为乙肝携带者。中位年龄为61.5岁（范围30 - 75岁）。总体疾病控制率为13%，15例患者中有2例疾病稳定超过8周。中位无进展生存期（PFS）为1.7（95%CI：1.67 - 1.73）个月，20例入组患者的中位总生存期（OS）为5.2（95%CI：3.3 - 12.0）个月。精氨酸充分耗竭（ADD）>2个月的患者与ADD≤2个月的患者相比，PFS显著延长（6.4个月对1.7个月；p = 0.01）。大多数不良事件（AE）为1/2级非血液学毒性。短暂性肝功能障碍（25%）是最常报告的严重AE，可能归因于疾病进展。药代动力学和药效学数据表明，Peg-rhAgr1可诱导快速且持续的精氨酸耗竭。入组患者的总体生活质量得到良好维持。Peg-rhAgr1在晚期HCC患者中耐受性良好，毒性特征良好。每周剂量1600 U/kg足以诱导ADD。ADD>2个月的患者记录到显著更长的PFS时间。
